Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
  • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
  • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
  • A61P23/02—Local anaesthetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• This invention relates to pharmaceutically useful compounds, in particular [(3-alkoxy-phenoxy)-ethyl]-dialkylamine derivatives, their use as medicaments, in particular anaesthetics (e.g. local anaesthetics), pharmaceutical compositions containing them and synthetic routes to their production.
• anaesthetics e.g. local anaesthetics
• [(4-Alkoxy-phenoxy)-ethyl]-morpholine and -piperidine derivatives are known as local anaesthetics from French Patent No. 1 173 136.
• certain 3-substituted phenoxyethylamine derivatives including (3-alkoxy-phenoxy)-ethyl]-diethylamine derivatives are known as local anaesthetics from U.S. Pat. No 3,105,854 and French Special Medicament Patent No. 302 M.
• R 1 represents C 3-5 alkyl
• R 2 and R 3 independently represent C 1-3 alkyl
• R 1 does not represent n-butyl i-butyl or n-pentyl
• the compounds of the invention or a pharmaceutically acceptable salt thereof (hereinafter referred to as “the compounds of the invention”).
• salts include nontoxic organic or inorganic acid addition salts, e.g. hydrochloride, hydrobromide, sulphate, hydrosulphate, nitrate, lactate, acetate, citrate, benzoate, succinate, tartrate, trifluoroacetate salts and the like.
• Preferred acid addition salts include hydrochloride salts.
• the compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomer may be separated using conventional techniques, e.g. chromatography or factional crystallisation.
• the various optical isomers ray be isolated by separation of a racemic or other mixture of the compounds using conventional e.g. fractional crystallisation or HPLC, techniques.
• the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisormers are included within the scope of the invention.
• Alkyl groups which R 1 , R 2 and R 3 may represent may be linear or branched. Typical alkyl groups which may be mentioned include methyl, ethyl, n-propyl, i-propyl, n-butyl i-butyl n-pentyl and i-pentyl and preferred alkyl groups are those wherein R 2 and R 3 do not both represent ethyl.
• Preferred compounds of the invention are those wherein R 1 represents n-propyl n-butyl or n-pentyl, R 2 represents methyl, ethyl or i-propyl, and R 3 represents i-propyl.
• More preferred compounds of the invention are those wherein R 1 represents n-propyl or n-butyl, R 2 represents methyl, ethyl or i-propyl, and R 3 represents i-propyl.
• R 1 represents n-propyl or n-butyl
• R 2 represents methyl or ethyl
• R 3 represents i-propyl
• Especially preferred compounds of the invention are those wherein R 1 represents n-propyl R 2 represents methyl or ethyl, and R 3 represents i-propyl.
• Most preferred compounds of the invention are those wherein R 1 represents n-propyl, R 2 represents methyl, and R 3 represents i-propyl.
• R 2 and R 3 are as hereinbefore defined, for example at elevated temperature (e.g. reflux) in the presence of a suitable organic solvent (e.g. toluene): or
• Hal represents Cl, Br or I and R 2 and R 3 are as hereinbefore defined, or an acid addition salt thereof, for example at elevated temperature (e.g. reflux) in the presence of a suitable base (e.g. sodium ethoxide) and an appropriate organic solvent (e.g. ethanol).
• a suitable base e.g. sodium ethoxide
• an appropriate organic solvent e.g. ethanol
• Hal is as hereinbefore defined.
• Compounds of formula II may be prepared in this way, for example at or around room temperature in the presence of a two phase solvent system and an appropriate ion pair extracting agent.
• Suitable organic solvents for the two phase system include excess alkyl dihalides of formula VI and suitable ion pair extracting agents include tetrabutylammonium hydroxide.
• Hal and R 1 are as hereinbefore defined, for example at elevated temperature (e.g. reflux) in the presence of a suitable base (e.g. sodium ethoxide) and an appropriate organic solvent (e.g. ethanol).
• a suitable base e.g. sodium ethoxide
• an appropriate organic solvent e.g. ethanol
• the compounds of the invention may be isolated from their reaction mitures using conventional techniques.
• the compounds of the invention are useful because they possess pharmacological activity. They are therefore indicated as pharmaceutcals.
• the compounds of the invention possess anaesthetic properties for example as demonstrated in the test described below. They are therefore useful as anaesthetics, in particular local anaesthetics and especially topically applied local anaesthetics.
• the compounds of the invention are thus indicated for the treatment of pain, including localised pain.
• the compounds of the invention will normally be administered parenterally, especially topically in the form of pharmaceutical formulations comprising the active ingredient in a pharmaceutically acceptable dosage form.
• Modes of topical administration of the compounds of the invention to the skin include emulsions, cream, lotions, ointments and skin patches.
• Compositions comprising the compounds of the invention for topical administration may include other ingredients commonly used in the parenteral administration of pharmaceutically-active compounds.
• a pharmaceutical formulation including a compound of formula I as, hereinbefore defined, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
• Formulations including the compounds of the invention may be prepared by techniques which are known per se. Usually the active substance will constitute between 0.5 and 15% by weight of the preparation, more specifically between 5 and 10% by weight.
• a method of treatment of a pain which method comprises administration of a therapeutically effective amount of a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to pain.
• the compounds of the invention have the advantage that they can be applied topically to intact skin, and also have a faster onset of action and a longer duration than compounds known in the prior art.
• Topical anaesthesia and analgesia during occlusion of intact skin in the guinea pig was studied by applying lipid formulations of local anaesthetics according to a method similar to that known from J. Pharmacol. Exp. Ther. 85,78 (1945) and detailed below.
• a twitching response was elicited by pricking the skin on the back of the animal with a cannula (22 G; Kifa, no point) or a von Frey filament (4.74; Semmes-Weinstein pressure aesthesiometer).
• a circular piece of gauze (1 to 8 layer) was saturated with test formulation in a thin plastic cup (4.5 cm 2 ) and applied to the middle of the back of the animal. The cup was then covered with self-adhesive (Fixomull®; BDF Beirsdorf AG, Hamburg, Germany) and the occlusion was finally protected with an elasticated bandage. Groups of two, three or six animals were used for each test formulation.
• the area was treated up to 15 minutes before removing the assembly.
• the treated area was subsequently wiped with a tissue and then examined for signs of local irritation.
• the skin which had been in contact with the formulation was pricked with a cannula or a von Frey filament under constant pressure six ties at different places and the presence or absence of twitching response was noted. This procedure was repeated at regular intervals of five minutes.
• the number of pricks not eliciting a response gave an indication of the degree of sensory anaesthesia or analgesia.
• the percentage anaesthesia/analgesia after the actual contact time was expressed as the total number of pricks not eliciting a response as a percentage of the total number of pricks.
• a solution of sodium ethoxide was prepared by adding sodium (11.5 g; 0.5 mol) to ethanol (500 ml). Resorcinol (55 g; 0.5 mol) was added to the stirred resultant solution, followed, half an hour later, by n-propylbromide (67.5 g; 0.55 mol). The reaction mixture was then heated to reflux for 3 hours. Upon cooling the resultant salt was removed by filtration and the solvent was evaporated. The residue was shaken between dilute aqueous sodium hydroxide and ether. The ether phase was extracted with dilute sodium hydroxide and the combined aqueous phases were neutralised using dilute aqueous hydrochloric acid.
• a solution of sodium ethoxide was prepared by adding sodium (2.3 g; 0.1 mol) to ethanol (100 ml; 1.63 mol).
• the appropriate 3-alkoxyphenol (0.05 mol; from Examples A to C above) was added to the resultant solution followed, half an hour's stirring later, by the appropriate 2-dialkylaminoethyl chloride hydrochloride (0.05 mmol) whereupon the reaction mixture was heated under reflux for between 1 and 10 hours.
• the resultant salt was removed by filtration and the solvent was evaporated.
• the residue was dissolved in an excess of dilute hydrochloric acid and the acid solution extracted with diethyl ether.
• the solution was then basified with dilute sodium hydroxide, the product extracted with diethyl ether and the extracts dried over potassium carbonate.
• the product was purified by distillation in vacuo.
• the compounds of Examples 1 to 9 were an tested in Test A above and were found to exhibit 100% anaesthesia/analgesia using 15 minutes contact time.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Anesthesiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

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Citations (5)

• 1996
  • 1996-10-14 AR ARP960104736A patent/AR004691A1/es unknown
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  • 1996-10-23 DE DE69620213T patent/DE69620213T2/de not_active Expired - Lifetime
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• 1998
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